A novel approach to evaluate alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy

Martinez-Valbuena, I.; Visanji, N. P.; Kim, A.; Lau, H. H. C.; So, R. W. L.; Alshimemeri, S.; Gao, A.; Seidman, M.; Luquin, M. R.; Watts, J. C.; Lang, A. E.; Kovacs, G. G.

doi:10.1101/2021.08.10.455800

bioRxiv · 10.1101/2021.08.10.455800

A novel approach to evaluate alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy

Martinez-Valbuena, I.·Visanji, N. P.·Kim, A.·Lau, H. H. C.·So, R. W. L.·Alshimemeri, S.·Gao, A.·Seidman, M.·Luquin, M. R.·Watts, J. C.·Lang, A. E.·Kovacs, G. G.

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Abstract

Several in vitro and in vivo findings have consistently shown that -synuclein derived from multiple system atrophy (MSA) subjects has more seeding capacity than Parkinsons disease-derived -synuclein. However, reliable detection of -synuclein derived from MSA using seeded amplification assays, such as the Real-Time Quaking-induced Conversion, has remained challenging. Here we demonstrate that the interaction of the Thioflavin T dye with -synuclein from MSA and Parkinsons disease patients can be modulated by the type of salt, pH, and ionic strength used to generate strain-specific reaction buffers. Employing this novel approach, we have generated a streamlined Real-Time Quaking-induced Conversion assay capable of categorizing MSA brains according to their -synuclein seeding behavior, and to unravel a previously unrecognized heterogeneity in seeding activity between different brain regions of a given individual that goes beyond immunohistochemical observations and provide a framework for future molecular subtyping of MSA.

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Martinez-Valbuena, I., Visanji, N. P., Kim, A., Lau, H. H. C., So, R. W. L., Alshimemeri, S., Gao, A., Seidman, M., Luquin, M. R., Watts, J. C., Lang, A. E., Kovacs, G. G.. 2021-08-10. A novel approach to evaluate alpha-synuclein seeding shows a wide heterogeneity in multiple system atrophy. https://doi.org/10.1101/2021.08.10.455800

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